US20170198002A1 - High Purity Low Endotoxin Carbohydrate (HPLE) Compositions, and Methods of Isolation Thereof - Google Patents

High Purity Low Endotoxin Carbohydrate (HPLE) Compositions, and Methods of Isolation Thereof Download PDF

Info

Publication number: US20170198002A1
Authority: US; United States
Prior art keywords: highly pure; solution; carbohydrate; composition; carbohydrate composition
Prior art date: 2014-06-13
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Abandoned

Application number

US15/316,614

Other languages

English (en)

Inventor

Bhaktavachalam Thiyagarajan

Martina COX

Nandu Deorkar

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Avantor Performance Materials LLC

Original Assignee

Avantor Performance Materials LLC

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2014-06-13

Filing date

2014-12-23

Publication date

2017-07-13

2014-12-23 Priority to US15/316,614 priority Critical patent/US20170198002A1/en

2014-12-23 Application filed by Avantor Performance Materials LLC filed Critical Avantor Performance Materials LLC

2017-03-10 Assigned to JEFFERIES FINANCE LLC reassignment JEFFERIES FINANCE LLC SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: APPLIED SILICONE COMPANY LLC, AVANTOR PERFORMANCE MATERIALS, LLC (FORMERLY KNOWN AS AVANTOR PERFORMANCE MATERIALS, INC.), NUSIL TECHNOLOGY LLC

2017-04-20 Assigned to AVANTOR PERFORMANCE MATERIALS, INC. reassignment AVANTOR PERFORMANCE MATERIALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEORKAR, NANDU, COX, Martina, THIYAGARAJAN, BHAKTAVACHALAM

2017-04-27 Assigned to AVANTOR PERFORMANCE MATERIALS, LLC reassignment AVANTOR PERFORMANCE MATERIALS, LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: AVANTOR PERFORMANCE MATERIALS, INC.

2017-07-13 Publication of US20170198002A1 publication Critical patent/US20170198002A1/en

2017-11-27 Assigned to APPLIED SILICONE COMPANY LLC, AVANTOR PERFORMANCE MATERIALS, LLC (FORMERLY AVANTOR PERFORMANCE MATERIALS, INC.), NUSIL TECHNOLOGY, LLC reassignment APPLIED SILICONE COMPANY LLC RELEASE (REEL 041966 / FRAME 0247) Assignors: JEFFERIES FINANCE LLC

2017-11-27 Assigned to APPLIED SILICONE COMPANY, LLC, AVANTOR PERFORMANCE MATERIALS, LLC (FORMERLY AVANTOR PERFORMANCE MATERIALS, INC.), NUSIL TECHNOLOGY, LLC reassignment APPLIED SILICONE COMPANY, LLC RELEASE (REEL 041966 / FRAME 0211) Assignors: JEFFERIES FINANCE LLC

2017-11-28 Assigned to GOLDMAN SACHS BANK USA, AS COLLATERAL AGENT reassignment GOLDMAN SACHS BANK USA, AS COLLATERAL AGENT SECURITY AGREEMENT Assignors: APPLIED SILICONE COMPANY LLC, AVANTOR PERFORMANCE MATERIALS, LLC, NUSIL TECHNOLOGY LLC, RELIABLE BIOPHARMACEUTICAL, LLC, THERAPAK, LLC

2017-11-29 Assigned to THE BANK OF NEW YORK MELLON TRUST COMPANY, N.A., AS NOTES COLLATERAL AGENT reassignment THE BANK OF NEW YORK MELLON TRUST COMPANY, N.A., AS NOTES COLLATERAL AGENT SECURITY AGREEMENT Assignors: APPLIED SILICONE COMPANY LLC, AVANTOR PERFORMANCE MATERIALS, LLC, NUSIL TECHNOLOGY LLC, RELIABLE BIOPHARMACEUTICAL, LLC, THERAPAK, LLC

2020-11-06 Assigned to THE BANK OF NEW YORK MELLON TRUST COMPANY, N.A., AS NOTES COLLATERAL AGENT reassignment THE BANK OF NEW YORK MELLON TRUST COMPANY, N.A., AS NOTES COLLATERAL AGENT SECURITY AGREEMENT (NOTES) Assignors: AVANTOR FLUID HANDLING, LLC, AVANTOR PERFORMANCE MATERIALS, LLC, NUSIL TECHNOLOGY LLC, RELIABLE BIOPHARMACEUTICAL, LLC, THERAPAK, LLC

2020-11-16 Assigned to APPLIED SILICONE COMPANY LLC, THERAPAK, LLC, NUSIL TECHNOLOGY LLC, RELIABLE BIOPHARMACEUTICAL, LLC, AVANTOR PERFORMANCE MATERIALS, LLC reassignment APPLIED SILICONE COMPANY LLC TERMINATION AND RELEASE OF SECURITY INTEREST IN PATENTS Assignors: THE BANK OF NEW YORK MELLON TRUST COMPANY, N.A.

Status Abandoned legal-status Critical Current

Links

150000001720 carbohydrates Chemical class 0.000 title claims abstract description 93
239000000203 mixture Substances 0.000 title claims abstract description 62
238000000034 method Methods 0.000 title claims abstract description 34
239000002158 endotoxin Substances 0.000 title claims description 55
238000002955 isolation Methods 0.000 title description 4
229920002873 Polyethylenimine Polymers 0.000 claims abstract description 27
238000004519 manufacturing process Methods 0.000 claims abstract description 9
238000005571 anion exchange chromatography Methods 0.000 claims abstract description 8
239000012501 chromatography medium Substances 0.000 claims abstract description 7
235000014633 carbohydrates Nutrition 0.000 claims description 87
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
239000012535 impurity Substances 0.000 claims description 21
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 17
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239000005720 sucrose Substances 0.000 claims description 16
238000002425 crystallisation Methods 0.000 claims description 15
230000008025 crystallization Effects 0.000 claims description 15
229930182830 galactose Natural products 0.000 claims description 9
239000000463 material Substances 0.000 claims description 9
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238000009472 formulation Methods 0.000 claims description 7
239000008194 pharmaceutical composition Substances 0.000 claims description 7
WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 6
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HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 5
HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 5
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XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
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NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
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RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
239000012480 LAL reagent Substances 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
239000013543 active substance Substances 0.000 description 2
125000000217 alkyl group Chemical group 0.000 description 2
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OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
229920000936 Agarose Polymers 0.000 description 1
229920000856 Amylose Polymers 0.000 description 1
235000016068 Berberis vulgaris Nutrition 0.000 description 1
235000021533 Beta vulgaris Nutrition 0.000 description 1
241000219310 Beta vulgaris subsp. vulgaris Species 0.000 description 1
108010078791 Carrier Proteins Proteins 0.000 description 1
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108010058683 Immobilized Proteins Proteins 0.000 description 1
GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
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240000000111 Saccharum officinarum Species 0.000 description 1
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235000021536 Sugar beet Nutrition 0.000 description 1
LUEWUZLMQUOBSB-UHFFFAOYSA-N UNPD55895 Natural products OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(OC2C(OC(OC3C(OC(O)C(O)C3O)CO)C(O)C2O)CO)C(O)C1O LUEWUZLMQUOBSB-UHFFFAOYSA-N 0.000 description 1
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BNABBHGYYMZMOA-AHIHXIOASA-N alpha-maltoheptaose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)O[C@H](O[C@@H]2[C@H](O[C@H](O[C@@H]3[C@H](O[C@H](O[C@@H]4[C@H](O[C@H](O[C@@H]5[C@H](O[C@H](O[C@@H]6[C@H](O[C@H](O)[C@H](O)[C@H]6O)CO)[C@H](O)[C@H]5O)CO)[C@H](O)[C@H]4O)CO)[C@H](O)[C@H]3O)CO)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O BNABBHGYYMZMOA-AHIHXIOASA-N 0.000 description 1
OCIBBXPLUVYKCH-QXVNYKTNSA-N alpha-maltohexaose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)O[C@H](O[C@@H]2[C@H](O[C@H](O[C@@H]3[C@H](O[C@H](O[C@@H]4[C@H](O[C@H](O[C@@H]5[C@H](O[C@H](O)[C@H](O)[C@H]5O)CO)[C@H](O)[C@H]4O)CO)[C@H](O)[C@H]3O)CO)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O OCIBBXPLUVYKCH-QXVNYKTNSA-N 0.000 description 1
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GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
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238000000354 decomposition reaction Methods 0.000 description 1
235000013681 dietary sucrose Nutrition 0.000 description 1
150000004683 dihydrates Chemical class 0.000 description 1
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239000003623 enhancer Substances 0.000 description 1
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239000012467 final product Substances 0.000 description 1
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239000008103 glucose Substances 0.000 description 1
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238000001361 intraarterial administration Methods 0.000 description 1
238000007918 intramuscular administration Methods 0.000 description 1
238000007912 intraperitoneal administration Methods 0.000 description 1
238000007913 intrathecal administration Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
238000004255 ion exchange chromatography Methods 0.000 description 1
239000007788 liquid Substances 0.000 description 1
238000004811 liquid chromatography Methods 0.000 description 1
DJMVHSOAUQHPSN-UHFFFAOYSA-N malto-hexaose Natural products OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(OC4C(C(O)C(O)C(CO)O4)O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 DJMVHSOAUQHPSN-UHFFFAOYSA-N 0.000 description 1
UYQJCPNSAVWAFU-UHFFFAOYSA-N malto-tetraose Natural products OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(O)C(CO)O2)O)C(CO)O1 UYQJCPNSAVWAFU-UHFFFAOYSA-N 0.000 description 1
LUEWUZLMQUOBSB-OUBHKODOSA-N maltotetraose Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@H](CO)O[C@@H](O[C@@H]2[C@@H](O[C@@H](O[C@@H]3[C@@H](O[C@@H](O)[C@H](O)[C@H]3O)CO)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-OUBHKODOSA-N 0.000 description 1
239000011159 matrix material Substances 0.000 description 1
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239000005017 polysaccharide Substances 0.000 description 1
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239000000741 silica gel Substances 0.000 description 1
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239000011780 sodium chloride Substances 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/02—Monosaccharides
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/04—Disaccharides
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/36—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving ionic interaction, e.g. ion-exchange, ion-pair, ion-suppression or ion-exclusion
- B01D15/361—Ion-exchange
- B01D15/363—Anion-exchange

Definitions

the present invention relates to high purity low endotoxin carbohydrates, and methods of making and using thereof.
Carbohydrates or sugars are useful as formulation enhancers for various active agents, such as in an injectable formulation involving an active agent such as a protein or peptide. Additionally, carbohydrates may be used as cell culture or fermentation supplement. Carbohydrates including mono, di, tri and polysaccharides such as glucose, sucrose, galactose, trehalose, maltose, amylose, maltohexaose, maltoheptaose, maltotetraose have been found to be particularly useful in these applications.
sugarcane Saccharum spp.
sugar beets Beta vulgaris
sugars have a number of impurities inherently associated therewith.
impurities include bacteria, protein, endotoxins, and various other plant-derived material.
Carbohydrates may be purified through many techniques, including by chromatographic separation. This can be done quickly and efficiently for laboratory scale synthesis, however, column chromatography and similar separation techniques become less useful as larger amounts of sugar are purified.
the size of the column, amount of solvents and stationary phase (e.g. silica gel) required and time needed for separation each increase with the amount of product purified, making purification from multi-kilogram scale synthesis unrealistic using column chromatography.
Another common purification technique for sugars involves the use of an ion-exchange resin. This technique can be tedious, requiring a tedious pre-treatment of the ion exchange resin. Many available ion exchange resins are also not necessarily able to separate the sugars from salts (e.g., NaCl). Acidic resins tend to remove both metal ions found in the crude product and amino- or imino-sugars from the solution and are therefore not useful. After purification of a sugar using an ion exchange resin, an additional step of concentrating the diluted aqueous solution is often required, and may be problematic as this step can cause decomposition of the sugar, which produces contaminants, and also reduces the yield.
salts e.g., NaCl
a specific ligand is covalently attached to a solid support matrix.
a sample containing the biological molecule which will specifically bind (absorb) to the immobilized ligand is brought into contact with the immobilized ligand.
the specifically bound molecule is eluted from the solid support by disrupting the specifically bound molecule-ligand interaction by one of several procedures, such as by changing the ionic strength or pH of elution buffers.
immobilized drugs, vitamins, peptides, hormones and the like may be used to isolate corresponding receptors or transport proteins.
Immobilized protein can serve to isolate other complementary or interacting proteins.
such a procedure can be used to separate particulate biological specimens, such as cell membranes and even intact cells bearing specific receptors. Use of such a procedure is also useful to purify polynucleotides, antigens, antibodies, virus, enzymes and the like.
solid based affinity support matrixes have been utilized to immobilize enzymes for use in reactions as catalysts and the like.
Ion-exchange chromatography is a type of affinity chromatography where ions and/or polar molecules in a composition facilitate separation based on their affinity to the ion exchanger. Fine particles having an ion exchanging group are widely used as a separating material in the field of pure water production and chromatography.
An anion exchanger having introduced therein polyethyleneimine as an ion exchanging group is used in the field of chelate resins, liquid chromatography for analyzing or isolating, for example, amino acids, peptide, protein, nucleic acids and saccharides.
anion exchange resins are available from various sources. They are prepared by attaching ligand to the solid support such as silica, Agarose or synthetic polymer.
the anion exchange resins based on polyethylenimine is made by attaching polyethylenimine to a synthetic polymer or silica.
an anion exchanger comprised of a fine particle having introduced therein polyethyleneimine
a method of introducing polyethyleneimine to a fine particle of a polymer having a halogenated alkyl group such as polychromethylstyrene as disclosed in U.S. Pat. No. 4,191,814 a method of introducing polyethyleneimine to an acrylate or methacrylate polymer having an epoxy group or a halogenated alkyl group as disclosed in U.S. Pat. No. 4,111,859; and a method of allowing an inorganic fine particle to adsorb polyethyleneimine and then crosslinking the adsorbed polyethyleneimine as disclosed in U.S. Pat. No. 4,245,005.
Endotoxins are small, stable, bacterially-derived hydrophobic molecules which can easily contaminate labware and whose presence can significantly impact both in vitro and in vivo experiments. Their presence is detected by the limulus amebocyte lysate (LAL) assay which can detect down to 0.01 Endotoxin Units (EU)/ml.
LAL limulus amebocyte lysate
EU Endotoxin Units
carbohydrate For carbohydrates used in pharmaceutical formulations or as a cell culture fermentation supplement, it is also critical to purify the carbohydrate such that is substantially free of endotoxins and other biological impurities such as DNA and RNA, heavy metals, related carbohydrate species, and bacterial contamination such as Ecoli.
the method includes passing an aqueous carbohydrate solution through an anion exchange chromatography column including a polyethylenimine (PEI) chromatographic media to obtain a purified solution, and isolating a highly pure carbohydrate composition from the purified solution.
the isolating step includes at least one of the steps of: i) crystallization with an alcohol, or ii) spray drying the purified solution.
the alcohol used in the crystallization step is ethanol.
the method further includes a filtration step of the aqueous carbohydrate solution before step passing it through the PEI column.
the filter has a pore size of about 0.4 microns to about 0.5 microns.
the highly pure carbohydrate composition is one selected from the group of sucrose, galactose, and trehalose. In an embodiment, the highly pure carbohydrate composition has endotoxin levels of less than 1 Endotoxin Unit per gram. In an embodiment, the highly pure carbohydrate composition has less than 5 ppb of elemental impurities such as lead. In another embodiment, the highly pure carbohydrate composition has less than 100 ppm of related carbohydrate species preferably less than 10 ppm.
a highly pure carbohydrate composition made by the methods disclosed herein.
the composition comprises an aqueous carbohydrate solution having an endotoxin value of less than 1 Endotoxin Units per gram.
the aqueous carbohydrate solution has an endotoxin value of less than 0.4 Endotoxin Units per gram.
the aqueous carbohydrate solution has an endotoxin value of less than 0.3 Endotoxin Units per gram, and in another embodiment a value of about 0.1 Endotoxin Units per gram.
the aqueous carbohydrate solution has been passed through an anion exchange chromatography column including a polyethylenimine (PEI) chromatographic media.
PEI polyethylenimine
the aqueous carbohydrate solution if further isolated after passing through the column by at least one of the steps of: i) crystallization with an alcohol, or ii) spray drying said purified solution.
the highly pure carbohydrate composition has less than 5 ppb of elemental impurities such as lead.
a formulation ingredient for a pharmaceutical composition is provided herein, particularly for a pharmaceutical formulation including a biologic.
the formulation ingredient is a highly pure carbohydrate composition as described herein.
the invention relates to composition and method to produce high purity low endotoxin (HPLE) carbohydrates such as Sucrose, Galactose, and Trehalose.
high purity low Endotoxin carbohydrates are the highly purified carbohydrates having very low levels of Endotoxin (less than 1 EU/g), a very low level of elemental impurities such as lead ( ⁇ 5 ppb), very low level of related carbohydrates species (less than 100 ppm), absence of bacterial contamination such as Ecoli and absence of RNA and DNA with no colored plant derived impurities.
the endotoxin level is 0.6 EU/g and most preferred composition with the endotoxin level of less than 0.1 EU/g.
the high purity low Endotoxin composition of carbohydrate is prepared by anion exchange chromatographic process followed by isolation using either (i) crystallization with ethanol or (ii) spray drying the purified sugar solution.
PEI Polymeric Polyethyleneimine
Crystalline sugar from the purified sugar solution is isolated either by adding alcohol to a concentrated sugar solution or spray drying the purified sugar solution.
the purpose of the invention is to show that high purity Endotoxin free sugars can be obtained using anion-exchange chromatographic media especially using polymeric chromatographic media containing polyethyleneimine.
the purified sugar solution can be isolated either by crystallization or by spray drying.
the HPLE carbohydrates with the composition mentioned above may be used in many applications, including without limitation: the formulation of injectable drug such as protein, peptides or similar chemical entities, or used as cell culture and fermentation supplement.
the subject invention concerns the use of polymeric anion exchange resin, preferably polyethyleneimine chromatographic resin for the purification of sucrose, galactose and trehaolse dihydrate.
polymeric anion exchange resin preferably polyethyleneimine chromatographic resin for the purification of sucrose, galactose and trehaolse dihydrate.
raw sugars was dissolved in DI water and passed onto the chromatography column packed with anion exchange reins such as Poly PEI resin at flow rate of 100-500 cm/hour, with a concentration range of 100-500 mg/ml.
Endotoxin and other anionic including biological impurities such as DNA and RNA being negatively charged at neutral pH strongly adsorbed to the column and purified sugar solution is collected.
the material collected was concentrated under heat using vacuum and ethanol was added and kept in ice for few hours.
concentration range of carbohydrates The concentration range of the carbohydrates varied from 500-800 mg/ml.
the preferred concentration range for sucrose is between 750-800 mg/ml, galactose is between 600-700 mg/ml and the trehalose dihydrate between 600-700 mg/ml.
the temperature of the concentrated solution before adding the alcohol The temperature of the concentrated solution before adding alcohol was between 10-60° C. However, preferred temperature range is 24-60° C. and most preferred temperature is 40° C. 3.
the volume of alcohol added ranges from 2.5 ⁇ to 3.0 ⁇ to that of volume of concentrated solution and preferably 3.0 ⁇ .
the crystallized material was isolated by filtration and washed with ethanol and dried under vacuum. Alternatively, the purified solution can also be spray dried for isolation.
compositions of the present invention are particularly useful in pharmaceutical compositions, such as parenteral compositions, including pharmaceutical compositions administered by methods other than enteral and topical administration, including by injection, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
parenteral compositions including pharmaceutical compositions administered by methods other than enteral and topical administration, including by injection, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
compositions including a biologic as an active ingredient it is very important, in particular for pharmaceutical compositions including a biologic as an active ingredient to have carbohydrate compositions of high purity. This is important because these carbohydrates are used for protein formulations that are administered through direct injection (parenteral formulation). The presence of even small amount of Endotoxin and other impurities will compromise the product purity, biological safety, shelf-life and patient safety.
sugars have a number of impurities inherently associated therewith.
impurities include without limitation bacteria, various proteins, endotoxins, and various other plant-derived material.
the impurities exist in a mixture with the carbohydrates, and still remain with carbohydrates through the extraction process because of various ionic forces, and other bonding forces between the impurities and the carbohydrate.
the highly purified carbohydrates resulting from the present inventive process provides a novel composition of matter not existent in nature.
the purified Sugar solution was concentrated to 700-800 mg/ml and cooled to 40°-60° C. Then 2 ⁇ to 3 ⁇ volume of Anhydrous Alcohol was added with stirring. Once the beaker contents reached room temperature, the beaker was chilled in an 0° C. to 20° C. ice bath for two to four hours with occasional stirring The crystals formed were washed with anhydrous Alcohol and dried under vacuum at 50° C. for 4 hours.
the crystals obtained using this procedure are free flowing and having particle size range from 80 micron to 500 micron.
Sucrose 760 mg/mL Sucrose was spiked with reducing sugars such as Fructose or Dextrose, and thereafter crystallized.
reducing sugars such as Fructose or Dextrose
a 7.5 kilogram (kg) sugar (sucrose) was dissolved in about 25 L purified water under stirring using overhead stirrer at about stirring speed of 50 rpm to produce a solution having solid content of about 23%.
the solution was stirred till clear solution was obtained.
the resultant solution was then spray dried using a spray dryer having fitted with rotary atomizer having size 100 mm at a speed of about 14000 rpm.
the inlet temperature of about 149-151° C., outlet temperature of about 100-108° C. and spray rate of about 5 L per hour was kept to produce spray dried sugar.
a yield of about 20-25% was obtained after completion of sugar spray drying trial.

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PCT/US2014/072117 WO2015191110A1 (fr)	2014-06-13	2014-12-23	Compositions de glucides à faible teneur en endotoxine de haute pureté et procédés pour les isoler

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EP (1)	EP3154994A4 (fr)
KR (1)	KR102445863B1 (fr)
CN (1)	CN106573948A (fr)
BR (1)	BR112016028637A2 (fr)
SG (2)	SG11201610316XA (fr)
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- 2014-12-23 BR BR112016028637A patent/BR112016028637A2/pt not_active IP Right Cessation
- 2014-12-23 CN CN201480079836.3A patent/CN106573948A/zh active Pending
- 2014-12-23 US US15/316,614 patent/US20170198002A1/en not_active Abandoned
- 2014-12-23 WO PCT/US2014/072117 patent/WO2015191110A1/fr active Application Filing
- 2014-12-23 EP EP14894668.4A patent/EP3154994A4/fr not_active Ceased
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SG11201610316XA (en)	2017-01-27
BR112016028637A2 (pt)	2017-08-22
KR20170018834A (ko)	2017-02-20
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